Design,Systhesis And Evaluation Of Indoleamine 2,3-dioxygenase Inhibitors

This thesis consists of two sections.First section: arylhydrazone derivatives as inhibitors of indoleamine 2,3-dioxygenase 1 inhibitors.Indoleamine 2,3-dioxygenase 1(IDO1)expression is associated with different prognosis factors and immunologic consequences in multiple human cancers.Furthermore,IDO1 is being extensively evaluated as a potential drug target in the field of cancer immune therapy.Several IDO1 inhibitors are being investigated in the clinical trial.To identify novel IDO inhibitors with suitable pharmacological and pharmaceutical properties,we have screened our in-house compound library and discovered the arylhydrazone type compound with IDO1 inhibition activity.In this study,we synthesized 24 aryhydrazone derivatives and evaluated their inhibitory activity against IDO1 and the cellular trptophan degradation pathway.Structure activity relationship was discussed and summarized.Among these derivatives,the most potent compound 4b displayed IC50 23.7 ?M.The compound mode of interaction with IDO1 was determined as reversible and noncompetitive.Taken together,this study provided a new motif for IDO1 inhibitor design.Further structural modification and more comprehensive investigation using this scaffold would certainly benefit the development of IDO1 pathway inhibitors.Second section: indole derivatives as inhibitors of indoleamine 2,3-dioxygenase 1 inhibitors.In recent years,several class of potent IDO1 inhibitors containing scaffolds of indole have been developed through structure-based design and high throughput screening.Furthermore,those findings should be considered in the design of indole-containing IDO inhibitors.In this study,scaffold hopping strategy was used to design and prepare a new set of 17 indole derivatives.Structural modification including installation of 3-aminoguanidine moiety,3-carboxamide moiety and 3-arylthio substituented moiety.Among these compound,compounds 7b,10 b,10c were found to show moderate IDO1 inhibition activity.